Method of producing 1,2-dihydro-3h-1,4-benzodiazepin-2-ones



.. Patented Atig.'4, 197o I v The reaction is supposed to proceed according to the 3,523,116 following scheme of reaction: METHOD OF PRODUCING 1,2-DIHYDRO- 3H-1,4-BENZODIAZEPIN-2-0NES Pasquale Domenico Sorrenfino, Kastrup, Denmark, 25-

signor to A/S Dumex (Dumex Ltd.), Copenhagen, Den- 5 mark, a o 0 No Drawing. Filed Nov. 15, 1967, Ser. No. 683,106 v Claims priority, applicationDenmark, Nov. 23, 1966, X

6,057/66 r Int. Cl. C07d 53/06 10 I US. Cl. 260-239.3 2 Claims 00 ABSTRACT on THE DISCLOSURE i invention relatesto ani ethodof producing 1,2- f f dihydro- 3H-1,4benaodiazepin-2-ones. in which a dihaloo o -c=o acetaniino-benzhydryl phthalimideis' reacted with an 7 e alkali metal alkoxide in alcoholicsolutiom-fl OH 0H:

X X \CHN/ \C=N/ This invention relates to a novel method of producing l l 1,2 dihydro 3H 1,4 benzodiazepin 2 ones of the formulai I 1 V R2 R i j 1 but it has not hitherto been possible to isolate the intermediate in brackets.

CH2 The starting materials are hitherto unknown products X g 4 which can be produced by reacting the corresponding aminobenzhydryl amine with phthalic acid anhydrideor I aminobenzhydryl chloride with potassium phtha1imide-, and reacting the resulting phthalimide with, for example, R2 dichloracetyl chloride.

The method of the invention is illustrated by the following example:

A suspension of 10 g. of Z-dichlor-acetyl-methylamino-S-chlorbenzhydryl phthalimide in 200 ml. of ethanol wherein X is hydrogen, halogen, a trifluoromethyl group, are refluxed fOI 2V2 hours with a solution Of 4.65 g. or a in group, R i an lk l group f not more h of sodium ethoxide in 100 ml. of ethanol. The reaction.

6 carbon atoms, and R i hydro n, halo a t ifl mixture is then cooled, and poured into 500 m1. of icemethyl group, or an alkyl or alkoxy group of not more Water, the P being adjusted) 7 than 6 carbon atoms. The compounds of this formula are After evaporation in vacuo to f i v m t known compounds having a ed ti muscle h reaction mixture is extracted with methylene chlorlde, and anticonvulsive eff t, and the organic phase is washed first with a 1 N aqueous It has surprisingly been f d that the Said compounds solution of sodium carbonate, and then with water, after can be prbduced in a ti f i yield by reacting a which it 1s dried over sodium sulphate, and the solvent haloacetaminobenzhydryl phthalimide of the formula: 15 dlstllled The yield is 2.8 g. of crude 7-ch1oro-l-methyl-S-phenyl- 1,2-dihydro-3H-1,4 benzodiazepin 2 one, which after 1 recrystallisation from isopropanol melts at 128-130 C. L To produce the starting material, a mixture of 33 g. of 2-methylamino-5-chlorbenzhydryl amine and 19.8 g. I C0 of phthalic acid anhydride is heated to 180-185" C. for X 15 minutes, after which the resulting melted mass is cooled, and recrystallized from ethanol, yielding 34.5 g. of Z-methylamino-S-chlorbenzhydryl phthalimide with CO melting point 191.2 191.9 c. Calcd for C H O N CI (percent): C, 70.2; H, 4.55; N, 7.44; Cl, 9.40. Found (percent): C, 69.97; H, 4.46; N, 7.42; 01, 9.30.

To a cooled solution of 21 g. of the said phthalimide in 260 ml. of benzene are added 18 g. of dichloracetyl wherein X, R and R are as hereinbefore defined, and chloride, and simultaneously a 2 N aqueous solution of Y is halogen, with an alkali metal alkoxide in alcoholic sodium hydroxyde at a rate to keep the temperature in solution. the reaction mixture between 5 and 10 C., and the pH washed with water, dried over sodium sulphate, and

concentrated to 80 ml. Then; 80 ml. of hexane are added,

and the mixture is stirred for one hour at 10 C. The thus precipitated crystals are filtered off and dried, yielding 25 g. of 2 dichloracetyl methylamino 5 chlorbenzhydryl phthalimide with melting point 206-207 C. A nitrogen test according to Kjeldahl gave 5.59% as against the theoretical 5.74%

In analogous manner, the following compounds can ,be prepared:

7-chlo1'o-l-ethyl-S-phenyl-1,2-dihydro-3H-1,4-

benzodiazepin-Z-one of M.P. 127-128 C. l-methyl-S-phenyl-l,2-dihydro-3H-1,4-benzodiazepin- 2-one of M.P. 154-155 C. 7'nitro-1-methyl-5-phenyl-1,2-dihydro-3H-l,4-

benzodiazepin-Z-one of M.P. 156-157 C. 7-bromo-l-methyl-5-(2'-fluorophenyl)-1,2-dihydro- 3H-1,4-benzodiazepin-2-one of M.P. 132 C. 7-chloro-1-methyl-5- (2-methylphen yl 1,2-dihydro- 3H-1,4-benzodiazepin-2-one of M.P. 138 C. 7-chloro-1-methy1-5-(2'-chloropheny1)-l,2-dihydro- 3H-1,4-benzodiazepin-2-one of M.P. 137-13 8 C. 7 -ch1oro-1-methyl-5-( 2-methoxyphenyl) 1,2-dihydro- 3H-1,4-benzodiazepin-2-one of M.P. 16 1-1615 C.

I claim: 1. The method of producing compounds of the formula:

wherein X is hydrogemhalogen', .trifluorometiiylr nitio; R is alkyl of from one to six carbon atoms; and R ishydrogen, haIOgem-trifluommethyh-aIkyl of from 'one to six carbon atoms, or alkoxy of from one to six carbon atoms; which comprises reacting a compound of the 5 formula R1 10 l q-o 0-0 HYz I References Cited I V UNITED STATES PATENTS 3,371,085 2/1968 Reeder et al. 260-259.}

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner us. 01. xii. 260326; 424-244 

